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Accurate measurement of traumatic intracranial hematoma volume is important for assessing disease progression and prognosis, as well as for serving as an important end-point in clinical trials aimed at preventing hematoma expansion. While the ABC/2 formula has traditionally been used for volume estimation in spontaneous intracerebral hemorrhage, its adaptation to traumatic hematomas lacks validation. This study aimed to compare the accuracy of ABC/2 with computer-assisted volumetric analysis (CAVA) in estimating the volumes of traumatic intracranial hematomas. We performed a dual-center observational study that included adult patients with moderate-to-severe traumatic brain injury. Volumes of intracerebral, subdural (SDHs), and epidural hematomas from admission computed tomography scans were measured using ABC/2 and CAVA, and compared using the Wilcoxon signed-rank test, Spearman's rank correlation, Lin's concordance correlation coefficient (CCC), and Bland-Altman plots. Prognostic significance for outcomes was evaluated through logistic and linear regression models. In total, 1,179 patients with 1,543 hematomas were included. Despite a high correlation (Spearman coefficients between 0.95 and 0.98) and excellent concordance (Lin's CCC from 0.89 to 0.96) between ABC/2 and CAVA, ABC/2 overestimated hematoma volumes compared with CAVA, in some instances exceeding 50 ml. Bland-Altman analysis highlighted wide limits of agreement, especially in SDH. While both methods demonstrated comparable accuracy in predicting outcomes, CAVA was slightly better at predicting craniotomies and midline shift. We conclude that while ABC/2 provides a generally reliable volumetric assessment suitable for descriptive purposes and as baseline variables in studies, CAVA should be the gold standard in clinical situations and studies requiring more precise volume estimations, such as those using hematoma expansion as an outcome.

Contusion expansion (CE) is a potentially treatable outcome predictor in traumatic brain injury (TBI), and a suitable end-point for hemostatic therapy trials. However, there is no consensus on the definition of clinically relevant CE, both in terms of measurement criteria (absolute vs. relative volume increase) and cutoff values. In light of this, the aim of this study was to assess the predictive abilities of different CE definitions on outcome. We performed a multi-center observational cohort study of adults with moderate-to-severe TBI treated in an intensive care unit. The exposure of interest was CE, defined as the absolute and relative volume change between the first and second computed tomography scan. The primary outcome was the Glasgow Outcome Scale (GOS) at 6-12 months post-injury, dichotomized into unfavorable (GOS ≤3) or favorable (GOS ≥4). The secondary outcome was all-cause mortality. In total, 798 patients were included, with a median duration of 7.0 h between the first and second CT scan. The median absolute and relative CE was 1.5 mL (interquartile range [IQR] 0.1-8.3 mL) and 100% (IQR 10-530%), respectively. Both CE forms were independently associated with unfavorable GOS. Absolute CE outperformed relative CE in predicting both unfavorable GOS (area under the curve [AUC]: 0.65 vs. 0.60, p  = 0.002) and all-cause mortality (AUC: 0.66 vs. 0.60, p  = 0.003). For dichotomized CE, absolute cutoffs of 1-10 mL yielded the best results. We conclude that absolute CE demonstrates stronger outcome correlation than relative CE. In studies focusing on lesion progression in TBI, it may be advantageous to use absolute CE as the primary outcome metric. For dichotomized outcomes, cutoffs between 1 and 10 mL are suggested, depending on the desired sensitivity-specificity balance.

Background: Penetrating trauma to the head and neck has increased during the past decade in Sweden. The aim of this study was to characterize these injuries and evaluate the outcomes for patients treated at a tertiary trauma center., Methods: Swedish trauma registry data were extracted on patients with head and neck injuries admitted to Karolinska University Hospital (Stockholm, Sweden) between 2011 and 2019. Outcome information was extracted from hospital records, with the primary endpoints focusing on the physiological outcome measures and the secondary endpoints on the surgical and radiological outcomes., Results: Of 1436 patients with penetrating trauma, 329 with penetrating head and neck injuries were identified. Of the 329 patients, 66 (20%) had suffered a gunshot wound (GSW), 240 (73%) a stab wound (SW), and 23 (7%) an injury from other trauma mechanisms (OTMs). The median age for the corresponding 3 groups of patients was 25, 33, and 21 years, respectively. Assault was the primary intent, with 54 patients experiencing GSWs (81.8%) and 158 SWs (65.8%). Patients with GSWs had more severe injuries, worse admission Glasgow coma scale, motor, scores, and a higher intubation rate at the injury site. Most GSW patients underwent major surgery (59.1%) as the initial procedure and were more likely to have intracranial hemorrhage (21.2%). The 30-day mortality was 45.5% (n = 30) for GSWs, 5.4% (n = 13) for SWs, and 0% (n = 0) for OTMs. There was an annual increase in the incidence and mortality for GSWs and SWs., Conclusions: Between 2011 and 2019, an increasing annual trend was found in the incidence and mortality from penetrating head and neck trauma in Stockholm, Sweden. GSW patients experienced more severe injuries and intracranial hemorrhage and underwent more surgical interventions compared with patients with SWs and OTMs., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Increased levels of extracellular vesicles (EVs) are associated with haemostatic disturbances in various clinical settings. However, their role in COVID-19 patients is still not fully clear. In the present study we investigated EVs in plasma from patients with COVID-19 and neurological symptoms in relation to the activation of coagulation., Methods: Nineteen COVID-19 patients with neurological symptoms and twenty-three aged-matched healthy individuals were included. Global coagulation assays were performed and levels of EVs were determined by flow-cytometry in plasma and cerebrospinal fluid (CSF)., Results: A procoagulant state characterized by significantly increased overall coagulation- (OCP) and overall haemostatic potential (OHP), diminished overall fibrinolytic potential (OFP) together with a denser fibrin structure was found in patients with COVID-19. Flow cytometry revealed elevated levels of plasma circulating EVs derived from neutrophils (MPO+) and platelets (CD61+), as well as EVs expressing phosphatidylserine (PS+) and complement component C5b-9 (TCC+) in patients with COVID-19 compared with controls. The concentrations of PS+, CD61+ and TCC+ EVs were positively correlated with OCP and OHP in COVID-19 patients. Moreover, we identified CD61+, MPO+ and endothelial cell-derived EVs, as well as EVs exposing PS and TCC in the CSF of patients suffering from neurological symptoms during COVID-19., Conclusion: The unique finding in this study was the presence of EVs in the CSF of COVID-19 patients with neurologic manifestations as well as higher expression of complement protein on circulating plasma EVs. EVs may indicate blood-brain barrier damage during SARS-COV-2 infection., (© 2023 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Monitoring protein biomarker levels in the cerebrospinal fluid (CSF) can help assess injury severity and outcome after traumatic brain injury (TBI). Determining injury-induced changes in the proteome of brain extracellular fluid (bECF) can more closely reflect changes in the brain parenchyma, but bECF is not routinely available. The aim of this pilot study was to compare time-dependent changes of S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), total Tau, and phosphorylated Tau (p-Tau) levels in matching CSF and bECF samples collected at 1, 3, and 5 days post-injury from severe TBI patients ( n  = 7; GCS 3-8) using microcapillary-based western analysis. We found that time-dependent changes in CSF and bECF levels were most pronounced for S100B and NSE, but there was substantial patient-to-patient variability. Importantly, the temporal pattern of biomarker changes in CSF and bECF samples showed similar trends. We also detected two different immunoreactive forms of S100B in both CSF and bECF samples, but the contribution of the different immunoreactive forms to total immunoreactivity varied from patient to patient and time point to time point. Our study is limited, but it illustrates the value of both quantitative and qualitative analysis of protein biomarkers and the importance of serial sampling for biofluid analysis after severe TBI., Competing Interests: No competing financial interests exist., (© I-Hsuan Lin et al., 2023; Published by Mary Ann Liebert, Inc.)

Background: Preventing intracranial hematoma expansion has been advertised as a possible treatment opportunity in traumatic brain injury (TBI). However, the time course of hematoma expansion, and whether the expansion affects outcome, remains poorly understood. In light of this, the aim of this study was to use 3D volume rendering to determine how traumatic intracranial hematomas expand over time and evaluate its impact on outcome., Methods: Single-center, population-based, observational cohort study of adults with moderate-to-severe TBI. Hematoma expansion was defined as the change in hematoma volume from the baseline computed tomography scan until the lesion had stopped progressing. Volumes were calculated by using semiautomated volumetric segmentation. Functional outcome was measured by using the 12 month Glasgow outcome scale (GOS)., Results: In total, 643 patients were included. The mean baseline hematoma volume was 4.2 ml, and the subsequent mean hematoma expansion was 3.8 ml. Overall, 33% of hematomas had stopped progressing within 3 h, and 94% of hematomas had stopped progressing within 24 h of injury. Contusions expanded significantly more, and for a longer period of time, than extra-axial hematomas. There was a significant dose-response relationship between hematoma expansion and 12 month GOS, even after adjusting for known outcome predictors, with every 1-ml increase in hematoma volume associated with a 6% increased risk of 1-point GOS deduction., Conclusions: Hematoma expansion is a driver of unfavorable outcome in TBI, with small changes in hematoma volume also impacting functional outcome. This study also proposes a wider window of opportunity to prevent lesion progression than what has previously been suggested., (© 2022. The Author(s).)

Traumatic brain injury (TBI) is the leading cause of death among the young, and has an increasing incidence among the elderly. In Sweden there are 20 000 new TBI cases each year, of which most are mild. The primary impact can lead to different types of brain hemorrhages, fractures and diffuse axonal injuries. The level of consciousness is used to define injury severity. Of all TBIs,  4-5 percent require surgical intervention. The primary impact initiates injury processes exacerbating the initial brain injury, and the goal of the acute management and neurointensive care treatment is to prevent these secondary insults. Among unconscious TBI patients, monitoring of intracranial pressure and cerebral perfusion pressure (CPP, defined as the difference between the mean arterial pressure and intracranial pressure) is routine. In this article we present an overview on different types of TBI, and describe the treatment of patients in the acute setting.

Background: Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive., Methods: Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points., Results: (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma., Conclusions: The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Preventing hemorrhage progression is a potential therapeutic opportunity in traumatic brain injury (TBI) management, but its use has been limited by fear of provoking vascular occlusive events (VOEs). However, it is currently unclear whether VOE actually affects outcome in these patients. The aim of this study was to determine incidence, risk factors, and clinical significance of VOE in patients with moderate-to-severe TBI. A retrospective observational cohort study of adults (≥15 years) with moderate-to-severe TBI was performed. The presence of a VOE during hospitalization was noted from hospital charts and radiological reports. Functional outcome, using the Glasgow Outcome Scale (GOS), was assessed at 12 months posttrauma. Univariate and multivariate logistic regressions were used for endpoint assessment. In total, 848 patients were included, with a median admission Glasgow Coma Scale of 7. A VOE was detected in 54 (6.4%) patients, of which cerebral venous thrombosis was the most common (3.2%), followed by pulmonary embolism (1.7%) and deep vein thrombosis (1.3%). Length of ICU stay ( p  < 0.001), body weight ( p  = 0.002), and skull fracture ( p  = 0.004) were independent predictors of VOE. VOE development did not significantly impact 12-month GOS, even after adjusting for potential confounders using propensity score matching. In conclusion, VOE in moderate-to-severe TBI patients was relatively uncommon, and did not affect 12-month GOS. This suggests that the potential benefit of treating bleeding progression might outweigh the risks of VOE., Competing Interests: None declared., (Thieme. All rights reserved.)

Studies show conflicting results regarding the prognostic significance of traumatic axonal injuries (TAI) in patients with traumatic brain injury (TBI). Therefore, we documented the presence of TAI in several brain regions, using different magnetic resonance imaging (MRI) sequences, and assessed their association to patient outcomes using machine learning. Further, we created a novel MRI-based TAI grading system with the goal of improving outcome prediction in TBI. We subsequently evaluated the performance of several TAI grading systems. We used a genetic algorithm to identify TAI that distinguish favorable from unfavorable outcomes. We assessed the discriminatory performance (area under the curve [AUC]) and goodness-of-fit (Nagelkerke pseudo-R 2 ) of the novel Stockholm MRI grading system and the TAI grading systems of Adams and associates, Firsching and coworkers. and Abu Hamdeh and colleagues, using both univariate and multi-variate logistic regression. The dichotomized Glasgow Outcome Scale was considered the primary outcome. We examined the MRI scans of 351 critically ill patients with TBI. The TAI in several brain regions, such as the midbrain tegmentum, were strongly associated with unfavorable outcomes. The Stockholm MRI grading system exhibited the highest AUC (0.72 vs. 0.68-0.69) and Nagelkerke pseudo-R 2 (0.21 vs. 0.14-0.15) values of all TAI grading systems. These differences in model performance, however, were not statistically significant (DeLong test, p  > 0.05). Further, all included TAI grading systems improved outcome prediction relative to established outcome predictors of TBI, such as the Glasgow Coma Scale (likelihood-ratio test, p  < 0.001). Our findings suggest that the detection of TAI using MRI is a valuable addition to prognostication in TBI.

Almost two-thirds of patients with severe traumatic brain injury (TBI) develop some form of hemostatic disturbance, which contributes to poor outcome. While the initial head injury often leads to impaired clot formation, TBI is also associated with an increased risk of thrombosis. Most likely there is a progression from early bleeding to a later prothrombotic state. In this paper, we systematically review the literature on the time course of hemostatic disruptions following TBI. A MEDLINE search was performed for TBI studies reporting the trajectory of hemostatic assays over time. The search yielded 5,049 articles, of which 4,910 were excluded following duplicate removal as well as title and abstract review. Full-text assessment of the remaining articles yielded 33 studies that were included in the final review. We found that the first hours after TBI are characterized by coagulation cascade dysfunction and hyperfibrinolysis, both of which likely contribute to lesion progression. This is then followed by platelet dysfunction and decreased platelet count, the clinical implication of which remains unclear. Later, a poorly defined prothrombotic state emerges, partly due to fibrinolysis shutdown and hyperactive platelets. In the clinical setting, early administration of the antifibrinolytic agent tranexamic acid has proved effective in reducing head-injury-related mortality in a subgroup of TBI patients. Further studies evaluating the time course of hemostatic disruptions after TBI are warranted in order to identify windows of opportunity for potential treatment options.

Background: Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls., Methods: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6-12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (Q A ), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort., Results: TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with Q A , among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR 2  = 7.4%) and complement factor B in serum (p = 0.003, ΔR 2  = 9.2%) were independent outcome predictors also following step-down modelling., Conclusions: This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.

Introduction . The acquired muscle paralysis associated with modern critical care can be of neurogenic or myogenic origin, yet the distinction between these origins is hampered by the precision of current diagnostic methods. This has resulted in the pooling of all acquired muscle paralyses, independent of their origin, into the term Intensive Care Unit Acquired Muscle Weakness (ICUAW). This is unfortunate since the acquired neuropathy (critical illness polyneuropathy, CIP) has a slower recovery than the myopathy (critical illness myopathy, CIM); therapies need to target underlying mechanisms and every patient deserves as accurate a diagnosis as possible. This study aims at evaluating different diagnostic methods in the diagnosis of CIP and CIM in critically ill, immobilized and mechanically ventilated intensive care unit (ICU) patients. Methods . ICU patients with acquired quadriplegia in response to critical care were included in the study. A total of 142 patients were examined with routine electrophysiological methods, together with biochemical analyses of myosin:actin (M:A) ratios of muscle biopsies. In addition, comparisons of evoked electromyographic (EMG) responses in direct vs. indirect muscle stimulation and histopathological analyses of muscle biopsies were performed in a subset of the patients. Results . ICU patients with quadriplegia were stratified into five groups based on the hallmark of CIM, i.e., preferential myosin loss (myosin:actin ratio, M:A) and classified as severe (M:A < 0.5; n = 12), moderate (0.5 ≤ M:A < 1; n = 40), mildly moderate (1 ≤ M:A < 1.5; n = 49), mild (1.5 ≤ M:A < 1.7; n = 24) and normal (1.7 ≤ M:A; n = 19). Identical M:A ratios were obtained in the small (4-15 mg) muscle samples, using a disposable semiautomatic microbiopsy needle instrument, and the larger (>80 mg) samples, obtained with a conchotome instrument. Compound muscle action potential (CMAP) duration was increased and amplitude decreased in patients with preferential myosin loss, but deviations from this relationship were observed in numerous patients, resulting in only weak correlations between CMAP properties and M:A. Advanced electrophysiological methods measuring refractoriness and comparing CMAP amplitude after indirect nerve vs. direct muscle stimulation are time consuming and did not increase precision compared with conventional electrophysiological measurements in the diagnosis of CIM. Low CMAP amplitude upon indirect vs. direct stimulation strongly suggest a neurogenic lesion, i.e., CIP, but this was rarely observed among the patients in this study. Histopathological diagnosis of CIM/CIP based on enzyme histochemical mATPase stainings were hampered by poor quantitative precision of myosin loss and the impact of pathological findings unrelated to acute quadriplegia. Conclusion . Conventional electrophysiological methods are valuable in identifying the peripheral origin of quadriplegia in ICU patients, but do not reliably separate between neurogenic vs. myogenic origins of paralysis. The hallmark of CIM, preferential myosin loss, can be reliably evaluated in the small samples obtained with the microbiopsy instrument. The major advantage of this method is that it is less invasive than conventional muscle biopsies, reducing the risk of bleeding in ICU patients, who are frequently receiving anticoagulant treatment, and it can be repeated multiple times during follow up for monitoring purposes.

Current accepted cerebrovascular reactivity indices suffer from the need of high frequency data capture and export for post-acquisition processing. The role for minute-by-minute data in cerebrovascular reactivity monitoring remains uncertain. The goal was to explore the statistical time-series relationships between intra-cranial pressure (ICP), mean arterial pressure (MAP) and pressure reactivity index (PRx) using both 10-s and minute data update frequency in TBI. Prospective data from 31 patients from 3 centers with moderate/severe TBI and high-frequency archived physiology were reviewed. Both 10-s by 10-s and minute-by-minute mean values were derived for ICP and MAP for each patient. Similarly, PRx was derived using 30 consecutive 10-s data points, updated every minute. While long-PRx (L-PRx) was derived via similar methodology using minute-by-minute data, with L-PRx derived using various window lengths (5, 10, 20, 30, 40, and 60 min; denoted L-PRx&#95;5, etc.). Time-series autoregressive integrative moving average (ARIMA) and vector autoregressive integrative moving average (VARIMA) models were created to analyze the relationship of these parameters over time. ARIMA modelling, Granger causality testing and VARIMA impulse response function (IRF) plotting demonstrated that similar information is carried in minute mean ICP and MAP data, compared to 10-s mean slow-wave ICP and MAP data. Shorter window L-PRx variants, such as L-PRx&#95;5, appear to have a similar ARIMA structure, have a linear association with PRx and display moderate-to-strong correlations (r ~ 0.700, p < 0.0001 for each patient). Thus, these particular L-PRx variants appear closest in nature to standard PRx. ICP and MAP derived via 10-s or minute based averaging display similar statistical time-series structure and co-variance patterns. PRx and L-PRx based on shorter windows also behave similarly over time. These results imply certain L-PRx variants may carry similar information to PRx in TBI.

Severe acute respiratory syndrome coronavirus 2 is responsible for the current COVID-19 pandemic resulting in an escalating number of cases and fatalities worldwide. Preliminary evidence from these patients, as well as past coronavirus epidemics, indicates that those infected suffer from disproportionate complement activation as well as excessive coagulation, leading to thrombotic complications and poor outcome. In non-coronavirus cohorts, evidence has accumulated of an interaction between the complement and coagulation systems, with one amplifying activation of the other. A pressing question is therefore if COVID-19 associated thrombosis could be caused by overactivation of the complement cascade? In this review, we summarize the literature on thrombotic complications in COVID-19, complement activation in coronavirus infections, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system is able to activate the coagulation cascade and platelets, inhibit fibrinolysis and stimulate endothelial cells. We also describe how these interactions see clinical relevance in several disorders where overactive complement results in a prothrombotic clinical presentation, and how it could be clinically relevant in COVID-19., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Brain protein biomarker clearance to blood in traumatic brain injury (TBI) is not fully understood. The aim of this study was to analyze the effect that a disrupted blood-brain barrier (BBB) had on biomarker clearance. Seventeen severe TBI patients admitted to Karolinska University Hospital were prospectively included. Cerebrospinal fluid (CSF) and blood concentrations of S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) were analyzed every 6-12 h for ∼1 week. Blood and CSF albumin were analyzed every 12-24 h, and BBB integrity was assessed using the CSF:blood albumin quotient (Q A ). We found that time-dependent changes in the CSF and blood levels of the two biomarkers were similar, but that the correlation between the biomarkers and Q A was lower for NSE (ρ = 0.444) than for S100B (ρ = 0.668). Because data were longitudinal, we also conducted cross correlation analyses, which indicated a directional flow and lag-time of biomarkers from CSF to blood. For S100B, this lag-time could be ascribed to BBB integrity, whereas for NSE it could not. Upon inferential modelling, using generalized least square estimation (S100B) or linear mixed models (NSE), Q A ( p  = 0.045), time from trauma ( p  < 0.001), time from trauma 2 ( p  = 0.023), and CSF biomarker levels ( p  = 0.008) were independent predictors of S100B in blood. In contrast, for NSE, only time from trauma was significant ( p  < 0.001). These findings are novel and important, but must be carefully interpreted because of different characteristics between the two proteins. Nonetheless, we present the first data that indicate that S100B and NSE are cleared differently from the central nervous system, and that both the disrupted BBB and additional alternative pathways, such as the recently described glymphatic system, may play a role. This is of importance both for clinicians aiming to utilize these biomarkers and for the pathophysiological understanding of brain protein clearance, but warrants further examination.

Despite improvements in medical triage and tertiary care, traumatic brain injury (TBI) remains associated with significant morbidity and mortality. Almost two-thirds of patients with severe TBI develop some form of hemostatic disturbance, which contributes to poor outcome. In addition, the complement system, which is abundant in the healthy brain, undergoes significant intra- and extracranial amplification following TBI. Previously considered to be structurally similar but separate systems, evidence of an interaction between the complement and coagulation systems in non-TBI cohorts has accumulated, with the activation of one system amplifying the activation of the other, independent of their established pathways. However, it is not known whether this interaction exists in TBI. In this review we summarize the available literature on complement activation following TBI, and the crosstalk between the complement and coagulation systems. We demonstrate how the complement system interacts with the coagulation cascade by activating the intrinsic coagulation pathway and by bypassing the initial cascade and directly producing thrombin as well. This crosstalk also effects platelets, where evidence points to a relationship with the complement system on multiple levels, with complement anaphylatoxins being able to induce disproportionate platelet activation and adhesion. The complement system also stimulates thrombosis by inhibiting fibrinolysis and stimulating endothelial cells to release prothrombotic microparticles. These interactions see clinical relevance in several disorders where a deficiency in complement regulation seems to result in a prothrombotic clinical presentation. Finally, based on these observations, we present the outline of an observational cohort study that is currently under preparation and aimed at assessing how complement influences coagulation in patients with isolated TBI.

In Sweden, there are currently no consensus guidelines aimed at the management of patients with mild traumatic brain injury (mTBI) in a primary care setting. The aim of this study was to assess the need for such guidelines by a web-based, multiple choice, case-based survey asking primary care physicians how they manage mTBI patients in the early (acute) and late (persistent symptoms) stage. The survey demonstrated a more uniform patient management pattern in the acute stage of mTBI, while it revealed a more heterogenous pattern in the later stage. This illustrates the need for consensus guidelines in the management of this patient category in the primary care setting, which was further substantiated by the request for such guidelines by 85% of the physicians participating in the survey.

[This corrects the article DOI: 10.1186/s40560-017-0223-2.]., (© The Author(s). 2020.)

Background: The prognosis of penetrating traumatic brain injury (pTBI) is poor yet highly variable. Current computerized tomography (CT) severity scores are commonly not used for pTBI prognostication but may provide important clinical information in these cohorts., Methods: All consecutive pTBI patients from two large neurotrauma databases (Helsinki 1999-2015, Stockholm 2005-2014) were included. Outcome measures were 6-month mortality and unfavorable outcome (Glasgow Outcome Scale 1-3). Admission head CT scans were assessed according to the following: Marshall CT classification, Rotterdam CT score, Stockholm CT score, and Helsinki CT score. The discrimination (area under the receiver operating curve, AUC) and explanatory variance (pseudo-R 2 ) of the CT scores were assessed individually and in addition to a base model including age, motor response, and pupil responsiveness., Results: Altogether, 75 patients were included. Overall 6-month mortality and unfavorable outcome were 45% and 61% for all patients, and 31% and 51% for actively treated patients. The CT scores' AUCs and pseudo-R 2 s varied between 0.77-0.90 and 0.35-0.60 for mortality prediction and between 0.85-0.89 and 0.50-0.57 for unfavorable outcome prediction. The base model showed excellent performance for mortality (AUC 0.94, pseudo-R 2 0.71) and unfavorable outcome (AUC 0.89, pseudo-R 2 0.53) prediction. None of the CT scores increased the base model's AUC (p > 0.05) yet increased its pseudo-R 2 (0.09-0.15) for unfavorable outcome prediction., Conclusion: Existing head CT scores demonstrate good-to-excellent performance in 6-month outcome prediction in pTBI patients. However, they do not add independent information to known outcome predictors, indicating that a unique score capturing the intracranial severity in pTBI may be warranted.

Brain-enriched protein biomarkers of tissue fate are being introduced clinically to aid in traumatic brain injury (TBI) management. The aim of this study was to determine how concentrations of six different protein biomarkers, measured in samples collected during the first weeks after TBI, relate to injury severity and outcome. We included neurocritical care TBI patients that were prospectively enrolled from 2007 to 2013, all having one to three blood samples drawn during the first 2 weeks. The biomarkers analyzed were S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), tau, and neurofilament-light (NF-L). Glasgow Outcome Score (GOS) was assessed at 12 months. In total, 172 patients were included. All serum markers were associated with injury severity as classified on computed tomography scans at admission. Almost all biomarkers outperformed other known outcome predictors with higher levels the first 5 days, correlating with unfavorable outcomes, and UCH-L1 (0.260, pseduo- R 2 ) displaying the best discrimination in univariate analyses. After adjusting for acknowledged TBI outcome predictors, GFAP and NF-L added most independent information to predict favorable/unfavorable GOS, improving the model from 0.38 to 0.51 pseudo- R 2 . A correlation matrix indicated substantial covariance, with the strongest correlation between UCH-L1, GFAP, and tau ( r  = 0.827-0.880). Additionally, the principal component analysis exhibited clustering of UCH-L1 and tau, as well as GFAP, S100B, and NSE, which was separate from NF-L. In summary, a panel of several different protein biomarkers, all associated with injury severity, with different cellular origin and temporal trajectories, improve outcome prediction models.

Traumatic brain injury (TBI) is a major cause of acquired disability globally, and effective treatment methods are scarce. Lately, there has been increasing recognition of the devastating impact of TBI resulting from sports and other recreational activities, ranging from primarily sport-related concussions (SRC) but also more severe brain injuries requiring hospitalization. There are currently no established treatments for the underlying pathophysiology in TBI and while neuro-rehabilitation efforts are promising, there are currently is a lack of consensus regarding rehabilitation following TBI of any severity. In this narrative review, we highlight short- and long-term consequences of SRCs, and how the sideline management of these patients should be performed. We also cover the basic concepts of neuro-critical care management for more severely brain-injured patients with a focus on brain oedema and the necessity of improving intracranial conditions in terms of substrate delivery in order to facilitate recovery and improve outcome. Further, following the acute phase, promising new approaches to rehabilitation are covered for both patients with severe TBI and athletes suffering from SRC. These highlight the need for co-ordinated interdisciplinary rehabilitation, with a special focus on cognition, in order to promote recovery after TBI., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Background: Cerebral microdialysis (CMD) is a valuable tool for monitoring compounds in the cerebral extracellular fluid (ECF). Glycerol is one such compound which is regarded as a marker of cell membrane decomposition. Notably, in some acutely brain-injured patients, CMD-glycerol levels rise without any other apparent indication of cerebral deterioration. The aim of this study was to investigate whether this could be due to an association between CMD-glycerol levels and the administration of glycerol-containing drugs., Methods: Microdialysis data were retrospectively retrieved from the hospital's intensive care unit patient data management system (PDMS). All patients who were monitored with CMD for ≥ 96 h were included. Administered drug doses were retrieved from the PDMS and converted to exact doses of glycerol. Cross-correlation analyses were performed between the free, metabolized as well as total administered dose of glycerol and the detrended and differenced CMD-glycerol concentration. These analyses were repeated for two sets of subgroups based upon the individual catheter's graphical trend and its location in relation to the lesion., Results: There was no significant correlation between the differenced CMD-glycerol levels and drug-administered glycerol. Furthermore, there was no significant correlation between CMD-glycerol and catheter location or graphical trend. However, if the CMD-glycerol levels were detrended, significant but clinically non-relevant correlations were identified (maximum correlation coefficient of 0.1 (0.04-0.15, 95% CI) at a lag of 7 h using the total administered dose of glycerol)., Conclusions: Glycerol-containing drugs routinely administered intravenously in the clinical setting appear to have a minimal and clinically insignificant effect on levels of glycerol in the cerebral ECF.

Introduction: Intracranial lesion development is a recognized complication in adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased mortality. As neurological assessment during ECMO treatment remains challenging, protein biomarkers of cerebral injury could provide an opportunity to detect intracranial lesion development at an early stage. The aim of this study was to determine if serially sampled S100B could be used to detect intracranial lesion development during ECMO treatment. Methods: We conducted an observational cohort study of all patients treated with ECMO at ECMO Center Karolinska (Karolinska University Hospital, Stockholm, Sweden) between January and August 2018, excluding patients who did not undergo a computerized tomography scan (CT) during treatment. S100B was prospectively collected at hospital admission and then once daily. The primary end-point was any type of CT verified intracranial lesion. Receiver operating characteristics (ROC) curves and Cox proportional hazards models were employed. Results: Twenty-nine patients were included, of which 15 (52%) developed an intracranial lesion and exhibited higher levels of S100B overall. S100B had a robust association with intracranial lesion development, especially during the first 200 hours following admission. The best area-under-curve (AUC) to predict intracranial lesion development was 40 and 140 hours following ECMO initiation, were a S100B level of 0.69μg/L had an AUC of 0.81 (0.628-0.997). S100B levels were markedly increased following the development of intracranial hemorrhage. Conclusions: Serial serum S100B samples in ECMO patients were both significantly elevated and had an increasing trajectory in patients developing intracranial lesions. Larger prospective trials are warranted to validate these findings and to ascertain their clinical utility.

Objective: To explore associations between pituitary dysfunction and clinical outcome at 12 months after traumatic brain injury and aneurysmal subarachnoid haemorrhage., Methods: Prospective cohort study of 82 patients with traumatic brain injury and 45 with aneurysmal subarachnoid haemorrhage, included at one neurointensive care unit. Baseline data comprised age, sex, Glasgow Coma Scale (GCS) score, S100B and pupil light reactions. Hormone data were collected in the neurointensive care unit and after 3, 6 and 12 months. Outcome was assessed with Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS), Rancho Los Amigos Cognitive Scale-Revised (RLAS-R) and Glasgow Outcome Scale Extended (GOSE)., Results: The most frequent hormonal deviations were hypogonadotropic hypogonadism (38%) and hypercortisolism (52%). At 12 months, performance on BNIS was impaired in 54% and GOSE in 37%. Controlling for baseline variables, low levels of gonadal hormones were associated with lower GOSE score (b = -0.80, p = 0.033), high levels of prolactin with lower RLAS (b = -1.42, p = 0.034) and high levels of serum insulin-like growth factor I (S-IGF-I) with lower RLAS level (b = -1.78, p = 0.002) and lower GOSE score (b = -1.49, p = 0.006)., Conclusion: These data suggest that pituitary dysfunctions during the first year after traumatic brain injury and aneurysmal subarachnoid haemorrhage may have clinically relevant, independent effects on clinical outcome at 12 months.

Background: Traumatic acute subdural hematomas (ASDHs) are associated with high rate of morbidity and mortality, especially in elderly individuals. However, recent reports indicate that the morbidity and mortality rates might have improved., Objective: To evaluate postoperative (30-d) mortality in younger vs elderly (≥70 yr) patients with ASDH. Comparing younger and elderly patients, the secondary objectives are morbidity patterns of care and 6 mo outcome according to Glasgow outcome scale (GOS). Finally, in patients with traumatic ASDH, we aim to provide prognostic variables., Methods: This is a large-scale population-based Scandinavian study including all neurosurgical departments in Denmark and Sweden. All adult (≥18 yr) patients surgically treated between 2010 and 2014 for a traumatic ASDH in Denmark and Sweden will be included. Identification at clinicaltrials.gov is NCT03284190., Expected Outcomes: We expect to provide data on potential differences between younger vs elderly patients in terms of mortality and morbidity. We hypothesize that elderly patients selected for surgery have a similar pattern of care as compared with younger patients. We will provide functional outcome in terms of GOS at 6 mo in younger vs elderly patients undergoing ASDH evacuation. Finally, clinical useful prognostic factors for favorable (GOS 4-5) vs unfavorable (GOS 1-3) will be identified., Discussion: An improved understanding of the clinical outcome, treatment and resource allocation, clinical course, and the prognostic factors of traumatic ASDH will allow neurosurgeons to make better treatment decisions., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Background: Intracranial hemorrhage (ICH) is a common complication in adults treated with extracorporeal membrane oxygenation (ECMO). Objectives: The aim of this study was to conduct a systematic review of the literature on the incidence, outcome and predictors of ECMO-associated ICH in adult patients, supplemented by a narrative review of its pathophysiology, management and future perspectives. Methods: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and www.clinicaltrials.gov were systematically searched. Studies that reported incidence, outcome or predictors of ECMO-associated ICH in adults (≥18 years) were eligible for inclusion. Results: Twenty five articles were included in the systematic review. The incidence of ECMO-associated ICH varied between 1.8 and 21 %. Mortality rates in ICH-cohorts varied between 32 and 100 %, with a relative risk of mortality of 1.27-4.43 compared to non-ICH cohorts. An increased risk of ICH was associated with ECMO-duration, antithrombotic therapy, altered intrinsic coagulation, renal failure, need of blood products, rapid hypercapnia at ECMO initiation, and even pre-ECMO morbidity. Conclusions: ICH is a common complication in adults treated with ECMO and associated with increased mortality. Treating an ICH during ECMO represents a balance between pro- and anticoagulatory demands. Neurosurgical treatment is associated with severe morbidity, but has been successful in selected cases. Future studies should aim at investigating the validity and feasibility of non-invasive monitoring in early detection of ECMO-associated ICH.

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

Background: Prehospital intubation in traumatic brain injury (TBI) focuses on limiting the effects of secondary insults such as hypoxia, but no indisputable evidence has been presented that it is beneficial for outcome. The aim of this study was to explore the characteristics of patients who undergo prehospital intubation and, in turn, if these parameters affect outcome., Material and Methods: Patients ≥15 years admitted to the Department of Neurosurgery, Stockholm, Sweden with TBI from 2008 through 2014 were included. Data were extracted from prehospital and hospital charts, including prospectively collected Glasgow Outcome Score (GOS) after 12 months. Univariate and multivariable logistic regression models were employed to examine parameters independently correlated to prehospital intubation and outcome., Results: A total of 458 patients were included ( n  = 178 unconscious, among them, n  = 61 intubated). Multivariable analyses indicated that high energy trauma, prehospital hypotension, pupil unresponsiveness, mode of transportation, and distance to the hospital were independently correlated with intubation, and among them, only pupil responsiveness was independently associated with outcome. Prehospital intubation did not add independent information in a step-up model versus GOS ( p  = 0.154). Prehospital reports revealed that hypoxia was not the primary cause of prehospital intubation, and that the procedure did not improve oxygen saturation during transport, while an increasing distance from the hospital increased the intubation frequency., Conclusion: In this modern trauma cohort, prehospital intubation was not independently associated with outcome; however, hypoxia was not a common reason for prehospital intubation. Prospective trials to assess efficacy of prehospital airway intubation will be difficult due to logistical and ethical considerations.

Introduction: The serum proteome following traumatic brain injury (TBI) could provide information for outcome prediction and injury monitoring. The aim with this affinity proteomic study was to identify serum proteins over time and between normoxic and hypoxic conditions in focal TBI., Material and Methods: Sprague Dawley rats (n=73) received a 3mm deep controlled cortical impact ("severe injury"). Following injury, the rats inhaled either a normoxic (22% O 2 ) or hypoxic (11% O 2 ) air mixture for 30min before resuscitation. The rats were sacrificed at day 1, 3, 7, 14 and 28 after trauma. A total of 204 antibodies targeting 143 unique proteins of interest in TBI research, were selected. The sample proteome was analyzed in a suspension bead array set-up. Comparative statistics and factor analysis were used to detect differences as well as variance in the data., Results: We found that complement factor 9 (C9), complement factor B (CFB) and aldolase c (ALDOC) were detected at higher levels the first days after trauma. In contrast, hypoxia inducing factor (HIF)1α, amyloid precursor protein (APP) and WBSCR17 increased over the subsequent weeks. S100A9 levels were higher in hypoxic-compared to normoxic rats, together with a majority of the analyzed proteins, albeit few reached statistical significance. The principal component analysis revealed a variance in the data, highlighting clusters of proteins., Conclusions: Protein profiling of serum following TBI using an antibody based microarray revealed temporal changes of several proteins over an extended period of up to four weeks. Further studies are warranted to confirm our findings., (Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite seemingly functional coagulation, hemorrhagic lesion progression is a common and devastating condition following traumatic brain injury (TBI), stressing the need for new diagnostic techniques. Multiple electrode aggregometry (MEA) measures platelet function and could aid in coagulopathy assessment following TBI. The aims of this study were to evaluate MEA temporal dynamics, influence of concomitant therapy, and its capabilities to predict lesion progression and clinical outcome in a TBI cohort., Material and Methods: Adult TBI patients in a neurointensive care unit that underwent MEA sampling were retrospectively included. MEA was sampled if the patient was treated with antiplatelet therapy, bled heavily during surgery, or had abnormal baseline coagulation values. We assessed platelet activation pathways involving the arachidonic acid receptor (ASPI), P2Y 12 receptor, and thrombin receptor (TRAP). ASPI was the primary focus of analysis. If several samples were obtained, they were included. Retrospective data were extracted from hospital charts. Outcome variables were radiologic hemorrhagic progression and Glasgow Outcome Scale assessed prospectively at 12 months posttrauma. MEA levels were compared between patients on antiplatelet therapy. Linear mixed effect models and uni-/multivariable regression models were used to study longitudinal dynamics, hemorrhagic progression and outcome, respectively., Results: In total, 178 patients were included (48% unfavorable outcome). ASPI levels increased from initially low values in a time-dependent fashion ( p  < 0.001). Patients on cyclooxygenase inhibitors demonstrated low ASPI levels ( p  < 0.001), while platelet transfusion increased them ( p  < 0.001). The first ASPI ( p  = 0.039) and TRAP ( p  = 0.009) were significant predictors of outcome, but not lesion progression, in univariate analyses. In multivariable analysis, MEA values were not independently correlated with outcome., Conclusion: A general longitudinal trend of MEA is identified in this TBI cohort, even in patients without known antiplatelet therapies. Values appear also affected by platelet inhibitory treatment and by platelet transfusions. While significant in univariate models to predict outcome, MEA values did not independently correlate to outcome or lesion progression in multivariable analyses. Further prospective studies to monitor coagulation in TBI patients are warranted, in particular the interpretation of pathological MEA values in patients without antiplatelet therapies.

Objectives: To compare the effect of time on cognitive impairments after Subarachnoid Haemorrhage and Traumatic Brain Injury and explore associations with baseline variables and global function., Methods: Patients with a Glasgow Coma Scale score of 3-13, were assessed at 3, 6 and 12 months post injury by use of BNIS for cognitive impairment, RLAS-R to categorise cognitive and behavioural function, Barthel Index to assess performance of daily living, HADS to screen for depression and anxiety, and EuroQoL-5D, LiSat-11 and Glasgow Outcome Scale Extended to assess global function., Results: BNIS T-scores did not differ significantly between groups and the proportion of patients with cognitive impairments was not significantly different at any time point. Cognition improved significantly between all time points in both groups except from 6 to 12 months after TBI. Generalised estimating equation showed non-significant signs of slower recovery of BNIS T-scores over time after SAH. Acute GCS scores were associated with BNIS T-scores after TBI but not after SAH. At 12 months, similar proportions of patients with SAH and TBI had good outcome., Conclusions: Cognitive improvements after SAH and TBI exhibit similarities and correlate with global function. GCS scores are associated with outcome after TBI but not after SAH.

Background: Intracranial hemorrhage (ICH) is a common complication in adults treated with extracorporeal membrane oxygenation (ECMO). The aim of this study was to identify predictors of outcome and investigate intervention strategies following ICH development in ECMO-treated adult patients., Methods: We conducted a retrospective review of adult patients (≥18 years) who developed an ICH during ECMO treatment at the Karolinska University Hospital (Stockholm, Sweden) between September 2005 and May 2017. Outcome was assessed by 30-day mortality and Glasgow Outcome Scale (GOS) after 6 months. The statistical analysis was supplemented by a case series of patients who were surgically treated for an ICH., Results: Sixty-five patients developed an ICH during ECMO treatment. 30-day mortality was 74% (n = 48), and was significantly associated with low level of consciousness at ICH diagnosis (p = 0.036), presence of intraparenchymal hematoma (IPH) (p = 0.049), IPH volume (p = 0.002), presence of intraventricular hemorrhage (p = 0.001), subarachnoid hemorrhage Fisher grade (p<0.001), hydrocephalus (p<0.001), midline shift (p = 0.026) and absent basal cisterns (p<0.001). Among the 30-day survivors (n = 17), 63% (n = 10) had favorable neurological outcome (GOS 4-5) after six months. Five patients were surgically treated for their ICH, some with dire hemorrhagic consequences, however one patient made a complete recovery., Conclusions: ICH in adult ECMO patients is associated with a high mortality rate. Outcome predictors can help to identify patients where ICH treatment is indicated. Treating a patient with an ICH during ECMO represents an intricate balance between pro- and anticoagulatory demands. Furthermore, surgical treatment is associated with several risks but may be indicated in life-threatening lesions. Prospective studies are warranted.

Purpose: Severe traumatic brain injury (TBI) is the predominant cause of death and disability following trauma. Several studies have observed improved survival in TBI patients exposed to β-blockers, however, the effect on functional outcome is poorly documented., Methods: Adult patients with severe TBI (head AIS ≥ 3) were identified from a prospectively collected TBI database over a 5-year period. Patients with neurosurgical ICU length of stay <48 h and those dying within 48 h of admission were excluded. Patients exposed to β-blockers ≤ 48 h after admission and who continued with treatment until discharge constituted β-blocked cases and were matched to non β-blocked controls using propensity score matching. The outcome of interest was Glasgow Outcome Scores (GOS), as a measure of functional outcome up to 12 months after injury. GOS ≤ 3 was considered a poor outcome. Bivariate analysis was deployed to determine differences between groups. Odds ratio and 95% CI were used to assess the effect of β-blockers on GOS., Results: 362 patients met the inclusion criteria with 21% receiving β-blockers during admission. After propensity matching, 76 matched pairs were available for analysis. There were no statistical differences in any variables included in the analysis. Mean hospital length of stay was shorter in the β-blocked cases (18.0 vs. 26.8 days, p < 0.01). The risk of poor long-term functional outcome was more than doubled in non-β-blocked controls (OR 2.44, 95% CI 1.01-6.03, p = 0.03)., Conclusion: Exposure to β-blockers in patients with severe TBI appears to improve functional outcome. Further prospective randomized trials are warranted.

Background: Traumatic brain injury (TBI) is a major contributor to morbidity and mortality. Computerized tomography (CT) scanning of the brain is essential for diagnostic screening of intracranial injuries in need of neurosurgical intervention, but may also provide information concerning patient prognosis and enable baseline risk stratification in clinical trials. Novel CT scoring systems have been developed to improve current prognostic models, including the Stockholm and Helsinki CT scores, but so far have not been extensively validated. The primary aim of this study was to evaluate the Stockholm and Helsinki CT scores for predicting functional outcome, in comparison with the Rotterdam CT score and Marshall CT classification. The secondary aims were to assess which individual components of the CT scores best predict outcome and what additional prognostic value the CT scoring systems contribute to a clinical prognostic model., Methods and Findings: TBI patients requiring neuro-intensive care and not included in the initial creation of the Stockholm and Helsinki CT scoring systems were retrospectively included from prospectively collected data at the Karolinska University Hospital (n = 720 from 1 January 2005 to 31 December 2014) and Helsinki University Hospital (n = 395 from 1 January 2013 to 31 December 2014), totaling 1,115 patients. The Marshall CT classification and the Rotterdam, Stockholm, and Helsinki CT scores were assessed using the admission CT scans. Known outcome predictors at admission were acquired (age, pupil responsiveness, admission Glasgow Coma Scale, glucose level, and hemoglobin level) and used in univariate, and multivariable, regression models to predict long-term functional outcome (dichotomizations of the Glasgow Outcome Scale [GOS]). In total, 478 patients (43%) had an unfavorable outcome (GOS 1-3). In the combined cohort, overall prognostic performance was more accurate for the Stockholm CT score (Nagelkerke's pseudo-R2 range 0.24-0.28) and the Helsinki CT score (0.18-0.22) than for the Rotterdam CT score (0.13-0.15) and Marshall CT classification (0.03-0.05). Moreover, the Stockholm and Helsinki CT scores added the most independent prognostic value in the presence of other known clinical outcome predictors in TBI (6% and 4%, respectively). The aggregate traumatic subarachnoid hemorrhage (tSAH) component of the Stockholm CT score was the strongest predictor of unfavorable outcome. The main limitations were the retrospective nature of the study, missing patient information, and the varying follow-up time between the centers., Conclusions: The Stockholm and Helsinki CT scores provide more information on the damage sustained, and give a more accurate outcome prediction, than earlier classification systems. The strong independent predictive value of tSAH may reflect an underrated component of TBI pathophysiology. A change to these newer CT scoring systems may be warranted.

Background: The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" ( t 1/2 ) in order to describe the "fall" rate in serum., Materials and Methods: Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations., Results: Following screening (10,389 papers), n  = 122 papers were included. The proteins S100B ( n  = 66) and NSE ( n  = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t 1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1-2 h) though possibly of non-cerebral origin. In contrast, the t 1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP ( n  = 18) appears to have t 1/2 of about 24-48 h in severe TBI. The protein UCH-L1 ( n  = 9) presents a t 1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L ( n  = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use., Conclusion: Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI.

Background: Intracranial hemorrhage (ICH) is a recognized complication of adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased morbidity and mortality. However, the predictors of ICH in this patient category are poorly understood. The purpose of this study was to identify predictors of ICH in ECMO-treated adult patients., Methods: We conducted a retrospective review of adult patients (≥18 years) treated with ECMO at the Karolinska University Hospital (Stockholm, Sweden) between September 2005 and June 2016, excluding patients with ICH upon admission or those who were treated with ECMO for less than 12 h. In a comparative analysis, the primary end-points were the difference in baseline characteristics and predictors of hemorrhage occurrence (ICH vs. non-ICH cohorts). The secondary end-point was difference in mortality between groups. Paired testing and uni- and multivariate regression models were applied., Results: Two hundred and fifty-three patients were included, of which 54 (21%) experienced an ICH during ECMO treatment. The mortality for patients with ICH was 81% at 1 month and 85% at 6 months, respectively, compared to 28 and 33% in patients who did not develop ICH. When comparing ICH vs. non-ICH cohorts, pre-admission antithrombotic therapy ( p  = 0.018), high pre-cannulation Sepsis-related Organ Failure Assessment (SOFA) coagulation score ( p  = 0.015), low platelet count ( p  < 0.001), and spontaneous extracranial hemorrhage ( p  = 0.045) were predictors of ICH. In a multivariate regression model predicting ICH, pre-admission antithrombotic therapy and low platelet count demonstrated independent risk association. When comparing the temporal trajectories for coagulation variables in the days leading up to the detection of an ICH, plasma antithrombin significantly increased per patient over time ( p  = 0.014). No other temporal trajectories were found., Conclusions: ICH in adult ECMO patients is associated with a high mortality rate and independently associated with pre-admission antithrombotic therapy and low platelet count, thus highlighting important areas of potential treatment strategies to prevent ICH development.

Purpose: Reports on long-term variations in pituitary function after traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH) diverge. The aim of the current study was to evaluate the prevalence and changes in pituitary function during the first year after moderate and severe TBI and SAH and to explore the relation between pituitary function and injury variables., Methods: Adults with moderate and severe TBI or SAH were evaluated at 10 days, 3, 6 and 12 months post-injury/illness. Demographic, clinical, radiological, laboratory, including hormonal data were collected., Results: A total of 91 adults, 56 (15 women/41 men) with TBI and 35 (27 women/8 men) with SAH were included. Perturbations in pituitary function were frequent early after the event but declined during the first year of follow-up. The most frequent deficiency was hypogonadotrope hypogonadism which was seen in approximately 25 % of the patients. Most of the variations were transient and without clinical significance. At 12 months, two patients were on replacement with hydrocortisone, four men on testosterone and one man on replacement with growth hormone. No relations were seen between hormonal levels and injury variables., Conclusions: Perturbations in pituitary function continue to occur during the first year after TBI and SAH, but only a few patients need replacement therapy. Our study could not identify a marker of increased risk of pituitary dysfunction that could guide routine screening. However, data demonstrate the need for systematic follow-up of pituitary function after moderate or severe TBI or SAH., Competing Interests: The authors have no competing interests to declare. Ethical approval The study was approved by Regional Ethical Review Board in Stockholm (No: 2008/3:9 2008/1574-31/3). Informed Consent Our research involved human participants who had obtained informed consent.

Background: In order to improve injury assessment of brain injuries, protein markers of pathophysiological processes and tissue fate have been introduced in the clinic. The most studied protein "biomarker" of cerebral damage in traumatic brain injury (TBI) is the protein S100B. The aim of this narrative review is to thoroughly analyze the properties and capabilities of this biomarker with focus on clinical utility in the assessment of patients suffering from TBI., Results: S100B has successfully been implemented in the clinic regionally (1) to screen mild TBI patients evaluating the need to perform a head computerized tomography, (2) to predict outcome in moderate-to-severe TBI patients, (3) to detect secondary injury development in brain-injured patients and (4) to evaluate treatment efficacy. The potential opportunities and pitfalls of S100B in the different areas usually refer to its specificity and sensitivity to detect and assess intracranial injury., Conclusion: Given some shortcomings that should be realized, S100B can be used as a versatile screening, monitoring and prediction tool in the management of TBI patients., Competing Interests: Compliance with ethical standards Funding Svenska läkaresällskapet (The Swedish Society of Medicine, SLS-587221) provided financial support to Eric Peter Thelin. The sponsor had no role in the design or conduct of this research. Conflict of interest Eric P. Thelin has received a lecture honorarium once in 2013 from Roche Diagnostics concerning the implementation of the Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults. These guidelines include S100B sampling so this could be considered to be a potential conflict of interest. Apart from that, all authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. Studies with human participants This article does not contain any studies with human participants performed by any of the authors.

Primary Objective: to investigate the presence of circulating microparticles (MPs) of brain tissue origin in the systemic and cerebrovenous blood of patients with severe traumatic brain injury (TBI)., Research Design: Prospective observational study in 15 consecutive patients with severe isolated TBI., Methods and Procedures: We repeatedly measured concentrations of MPs expressing glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and aquaporin-4 (AQP4), in arterial and cerebrovenous blood at admittance to hospital and up to 72 hours after the injury., Main Outcomes and Results: Concentrations of MPs expressing GFAP and AQP4 were significantly higher in the TBI group compared with healthy controls: GFAP 2.0 [1.1-7.9] vs. 1.3 [1-2.1] × 10 6 /mL, p < 0.001; AQP4 0.1 [0.07-0.22] vs. 0.08 [0.06-0.11] × 10 6 /mL, p < 0.001 (median, range). No transcranial gradients were found. Levels of NSE-expressing MPs were also higher in the TBI group compared with healthy controls: 0.4 [0.25-2.1] vs. 0.26 [0.13-0.98] × 10 6 /mL, p < 0.05; however, regarding NSE-positive non-platelet MPs, there were no differences between patients and controls., Conclusions: Patients with TBI have higher numbers of brain-derived MPs. Further studies are needed, however, to identify specific and sensitive MP markers of brain injury.

Background: In order to improve assessment and outcome prediction in patients suffering from traumatic brain injury (TBI), cerebral protein levels in serum have been suggested as biomarkers of injury. However, despite much investigation, biomarkers have yet to reach broad clinical utility in TBI. This study is a 9-year follow-up and clinical experience of the two most studied proteins, neuron-specific enolase (NSE) and S100B, in a neuro-intensive care TBI population. Our aims were to investigate to what extent NSE and S100B, independently and in combination, could predict outcome, assess injury severity, and to investigate if the biomarker levels were influenced by extracranial factors., Methods: All patients treated at the neuro-intensive care unit at Karolinska University Hospital, Stockholm, Sweden between 2005 and 2013 with at least three measurements of serum S100B and NSE (sampled twice daily) were retrospectively included. In total, 417 patients fulfilled the criteria. Parameters were extracted from the computerized hospital charts. Glasgow Outcome Score (GOS) was used to assess long-term functional outcome. Univariate, and multivariate, regression models toward outcome and what explained the high levels of the biomarkers were performed. Nagelkerke's pseudo-R(2) was used to illustrate the explained variance of the different models. A sliding window assessed biomarker correlation to outcome and multitrauma over time., Results: S100B was found a better predictor of outcome as compared to NSE (area under the curve (AUC) samples, the first 48 hours had Nagelkerke's pseudo-R(2) values of 0.132 and 0.038, respectively), where the information content of S100B peaks at approximately 1 day after trauma. In contrast, although both biomarkers were independently correlated to outcome, NSE had limited additional predictive capabilities in the presence of S100B in multivariate models, due to covariance between the two biomarkers (correlation coefficient 0.673 for AUC 48 hours). Moreover, NSE was to a greater extent correlated to multitrauma the first 48 hours following injury, whereas the effect of extracerebral trauma on S100B levels appears limited to the first 12 hours., Conclusions: While both biomarkers are independently correlated to long-term functional outcome, S100B is found a more accurate outcome predictor and possibly a more clinically useful biomarker than NSE for TBI patients.

Background: An understanding of the kinetics of a biomarker is essential to its interpretation. Despite this, little kinetic modelling of blood biomarkers can be found in the literature. S100b is an astrocyte related marker of brain injury used primarily in traumatic brain injury (TBI). Serum levels are expected to be the net result of a multi-compartmental process. The optimal sample times for TBI prognostication, and to follow injury development, are unclear. The purpose of this study was to develop a kinetic model to characterise the temporal course of serum S100b concentration after primary traumatic brain injury., Methods: Data of serial serum S100b samples from 154 traumatic brain injury patients in a neurointensive care unit were retrospectively analysed, including only patients without secondary peaks of this biomarker. Additionally, extra-cranial S100b can confound samples earlier than 12 h after trauma and were therefore excluded. A hierarchical, Bayesian gamma variate kinetic model was constructed and the parameters estimated by Markov chain Monte Carlo sampling., Results: We demonstrated that S100b concentration changes dramatically over timescales that are clinically important for early prognostication with a peak at 27.2 h (95 % credible interval [25.6, 28.8]). Baseline S100b levels was found to be 0.11 μg/L (95 % credible interval [0.10, 0.12])., Conclusions: Even small differences in injury to sample time may lead to marked changes in S100b during the first days after injury. This must be taken into account in interpretation. The model offers a way to predict the peak and trajectory of S100b from 12 h post trauma in TBI patients, and to identify deviations from this, possibly indicating a secondary event. Kinetic modelling, providing an equation for the peak and projection, may offer a way to reduce the ambiguity in interpretation of, in time, randomly sampled acute biomarkers and may be generally applicable to biomarkers with, in time, well defined hits.